The presence of a-synuclein brain aggregates are a hallmark of a spectrum of neurodegenerative disorders, including Parkinson disease, Lewy body dementia and multiple system atrophy, and are associated with disease severity. Several studies suggest that this ?a-synuclein pathology may spread during disease progression by a self-templating mechanism and that nervous tissue containing aggregated a-synuclein could be a risk for disease transmission similar to prion disease. However, we recently demonstared that a non-??- synuclein factor enriched in central nervous tissue-derived white matter is sufficient to induce the progressive formation of a-synuclein inclusion pathology that can mimic prion-like transmission of a-synuclein pathology. These observations suggest the presence of a yet unidentified factor that can trigger a-synucleinopathy, similar to protein X, a putative auxiliary factor in prionopathies. Furthermore, this factor may have a pathogenic role in human disease. To resolve critical issues at the core of whether synucleinopathies should be re-classified as prion disorders and to elucidate mechanisms involved in disease progression we propose the following aims: 1) characterize the biochemical properties of the non-a-synuclein component that can trigger the progressive formation of a-synuclein, 2) determine whether a-synuclein aggregates can truely exhibit properties expected of classical prions, and 3) determine the relative prion-like transmission properties of central nervous tissue from patients with multiple system atrophy and Lewy body dementia, two phenotypically distinctive a-synucleinopathies. These highly integrated aims will provide important mechanistic and biologically relevant insights into the mechanisms and risk of pathology transmission from tissues containing a-synucleinopathies.